Neurotoxicology Flashcards
measures of brain function
in animal models there are tests for consciousness, behaviours, cognitive function, and electrophysiology tests
EEGs to see overall electrical activity
fMRI for oxygenated blood levels
other end points are subjective, e.g., headache, nausea
Biochemical biomarkers for CNS
Neuron special enolase
neurofilament light chain (good for alzheimers and CNS injury)
Tau-proteins are associated with neurodegenerative diseases and brain injury
Beta-amyloid precursors
inflammatory indicators, e.g., IL-1, IL6- C-Reactive protein (these are less specific to CNS)
GFAP for glial injury and UCH-L1 can both be increased post stroke
BBB role in toxicology
acts to keep out many toxins, however for toxins that can cross the BBB, there is very little antioxidant defense within the CNS
infection, trauma, hypoxia, and stroke impair the BBB
mechanisms and treatment of ammonia toxicity in CNS
Ammonia generated in the liver reacts with glutamate in astrocytes to produce glutamine (by glutamine synthase)
The osmotic activity of glutamine causes astrocyte swelling - cerebral oedema
Furthermore, ammonia activates NMDARs causing excitotoxicty - cell death. also associated with neuropsychiatric disorders and alzheimers. Meth toxicity is in part mediated by ammonia.
Treatment with glutamine synthase inhibitors and lactulose. lactulose acidifies the gut, retaining more ammonia there. NMDA antagonists can also reduce ammonia damage
toxicity of cycads and cyanobacteria mechanism
produce BMAA which activates neuronal glutamate receptors and may also be incorporated into proteins.
causes limb muscle atrophy, neurodegeneration and behavioural dysfunction. linked with ALS development
BMAA also accumulates in shellfish (particularly higher in food chain)
Excitotoxicity overview
mediated by over activation of glutamatergic receptors (NMDA, AMPA, kainate) causing sodium and calcium influx.
This causes mitochondrial damage
NMDA antagonists are used to prevent this excitotoxicity, e.g., MK-801 and ketamine
Chloroform CNS toxicity mechanism
can cause unconsciousness, renal and hepatic toxicity,
Mechanism of anaesthesia through GABA stimulation and inhibition of sodium channels in gluatminergic neurones (reduces glutamate release). also affects nAChRs and glycine receptors
Death from respiratory depression
GABA-A mediated toxicity
Death generally from respiratory depression
e.g., ethanol, GHB (agonist) and barbiturates (PAM and agonists at higher doses)
barbiturates also antagonist at all glutamate receptors
opioids toxicity
generally through respiratory depression - reversible with naloxone.
opioids also likely have antagonism at NMDA receptors leading to respiratory depression
Parkinsons-like toxicity example and mechanism
6-hydroxydopamine (acute) and MPTP can cause parkinson-like toxicity and even permanent parkinsonism
MPTP cross the BBB and is converted to MPP+ by MAO-B
MPP+ is internalised (by DAT) into dopaminergic neurones mitochondria and then inhibits complex-1 of the respiratory chain leading to free radical generation and lower [ATP]
MAO-B inhibitors as treatment
lead toxicity mechanism and treatment
environmental contaminants and found in infrastructure
NMDA antagonist and is substituted for calcium in many biological reactions (e.g., bone calcification)
also inhibits NaK-ATPase and mitochondrial Ca2+ release - apoptic
Causes lead encephalopathy - headache behaviour changes, amnesia, hallucinations, mental dullness
chelation therapy for treatment like dimercaprol and penicillamine
Aluminium toxicity mechanism
stimulates iron initiated lipid peroxidation.
at low doses stimulates AChE but at higher doses inhibits it.
increases glutamate - excitotoxicity
develops alzheimers
Domoic acid mechanism
found in blue mussels, red algae, and plankton
causes amnesiac shellfish poisoning
causes GI symptoms early on and then leads to CNS toxicity - nausea, vomiting, BP instability, headache, diarrhoea, arrhythmia, CNS dysfunction, memory loss, seizures, coma, etc…
Has similar chemical structure to kainic acid - activates at glutamatergic receptors - excitotoxicity
